In the last 50 years, only 236 people have been infected with anthrax in the United States. Although primarily a veterinary disease, the recent anthrax bioterrorism threat suggests that the incidence of anthrax in humans likely will increase. The disease is initiated by contact with anthrax spores and manifests as inhaled, cutaneous, and gastrointestinal forms, all of which can be fatal. Inhalation anthrax, however, has the highest mortality, with a survival rate of only 60% in the recent U.S. bioterrorism incidents (see, e.g., Ingelsby et al., JAMA, 287, 2236-2252 (2002)).
The pathogenesis of many bacterial infections is dependent on extracellular proteins known as exotoxins. Exotoxins cause pathogenesis by a number of mechanisms, including tissue invasion, cell lysis, effects on neurotransmitter uptake and release, and disruption of cellular homeostasis. With respect to Bacillus anthracis, the causative agent of anthrax, pathogenesis is elicited by three exotoxins known as protective antigen (PA), edema factor (EF), and lethal factor (LF). PA is a proteolytically activated heptamer which binds to a specific cellular receptor and facilitates intracellular translocation of EF and/or LF. LF is a metalloprotease which acts on a variety of substrates including mitogen-activated protein kinase. EF induces fluid loss, possibly through elevation of intracellular cyclic AMP (camp) levels. Bacillus anthracis exotoxins are binary in that two Polypeptides are required for toxicity.
The anthrax vaccine that is currently available in the United States consists of a cell-free filtrate of a nonencapsulated attenuated strain of B. anthracis (Bioport Corporation, Lansing, Mich.), of which protective antigen is the major component (see, e.g., Puziss et al., J. Bacteriol., 85, 230-236 (1962), and Puziss et al., Appl. Microbiol., 11, 330-334 (1963)). The safety and efficacy of this vaccine in humans, however, remains the focus of intense investigation (see, e.g., Inglesby et al., supra). Indeed, several drawbacks associated with the vaccine have been reported, including the need for frequent boosters, the apparent inability to protect adequately against certain strains of B. anthracis, and occasional local immunogenicity (see, e.g., Ivins et al., Eur. J. Epidemiol., 4, 12-19 (1988)). In addition, an experimental vaccine based on recombinant PA with an Alhydrogel adjuvant is currently being developed by the U.S. Army, but has not yet been tested in humans (see, e.g., Ivins et al., Vaccine, 16, 1141-1148 (1998)).
Accordingly, there remains a need for alternative compositions and methods for protection against anthrax infection that elicit a rapid and efficient immune response in a broad spectrum of the population. The invention provides such a composition and method. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.